Abstract

Background: The transcription factor MYC is a critical regulator of diverse cellular processes, including bothreplication and apoptosis. Differences in MYC-regulated gene expression responsible for such opposing outcomesin vivo remain obscure. To address this we have examined time-dependent changes in global gene expression intwo transgenic mouse models in which MYC activation, in either skin suprabasal keratinocytes or pancreatic islet bcells,promotes tissue expansion or involution, respectively.Results: Consistent with observed phenotypes, expression of cell cycle genes is increased in both models (albeitenriched in b-cells), as are those involved in cell growth and metabolism, while expression of genes involved incell differentiation is down-regulated. However, in b-cells, which unlike suprabasal keratinocytes undergoprominent apoptosis from 24 hours, there is up-regulation of genes associated with DNA-damage response andintrinsic apoptotic pathways, including Atr, Arf, Bax and Cycs. In striking contrast, this is not the case for suprabasalkeratinocytes, where pro-apoptotic genes such as Noxa are down-regulated and key anti-apoptotic pathways (suchas Igf1-Akt) and those promoting angiogenesis are up-regulated. Moreover, dramatic up-regulation of steroidhormone-regulated Kallikrein serine protease family members in suprabasal keratinocytes alone could furtherenhance local Igf1 actions, such as through proteolysis of Igf1 binding proteins.Conclusions: Activation of MYC causes cell growth, loss of differentiation and cell cycle entry in both b-cells andsuprabasal keratinocytes in vivo. Apoptosis, which is confined to b-cells, may involve a combination of a DNAdamageresponse and downstream activation of pro-apoptotic signalling pathways, including Cdc2a and p19Arf/p53, and downstream targets. Conversely, avoidance of apoptosis in suprabasal keratinocytes may result primarilyfrom the activation of key anti-apoptotic signalling pathways, particularly Igf1-Akt, and induction of an angiogenicresponse, though intrinsic resistance to induction of p19Arf by MYC in suprabasal keratinocytes may contribute.